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충남대학교 의과대학 내과학교실 (호흡기내과)

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Biochem. Biophys. Res. Commun., Volume 474, Issue 1, 20 May 2016, Pages 154-160 | https://doi.org/10.1016/j.bbrc.2016.04.089 Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance

Jeong Eun Lee ^{a 1}, Hee Sun Park ^{a 1}, Dahye Lee ^a, Geon Yoo ^b, Tackhoon Kim ^c, Haeyon Jeon ^c, Min-Kyung Yeo ^d, Choong Sik Lee ^d, Jae Young Moon ^a, Sung Soo Jung ^a, Ju Ock Kim ^a, Sun Young Kim ^a, Dong Il Park ^a, Yeon Hee Park ^a, Jae Cheol Lee ^e, In-Jae Oh ^f, Dae Sik Lim ^b, Chaeuk Chung ^{a *}

^aDepartment of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea
^bDepartment of Biological Sciences, Seoul National University, Seoul 151-742, South Korea
^cNational Creative Research Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology(KAIST), Daejeon 34141, South Korea
^dDepartment of Pathology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea
^eDepartment of Oncology, College of Medicine, University of Ulsan Asan Medical Center, Seoul 138-736, South Korea
^fDepartment of Internal Medicine, Chonnam National University Hwasun Hospital 322 Seoyangro, Hwasun-eup, Hwasun, Jeonnam, 519-809, South Korea

¹These authors contributed equally

^*Corresponding author: correspondence to Chaeuk Chung

Abstract

The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired resistance after EGFR-TKI treatment, and primary resistance marked by cancer cell's dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.

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